Angiogenesis is defined as the formation of new capillary blood vessels from preexisting micro-vessels. Normal angiogenesis occurs during embryogenic development, tissue remodeling, organ growth, wound healing and female reproductive cycles (corpus luteum development) under tight physiological regulation (Folkman and Cotran, Int. Rev. Exp. Patho., 16:207-248, 1976). Generally, angiogenesis involves the proteolysis of the blood vessel basement membrane by proteases, followed by the migration, proliferation and differentiation of endothelial cells to form tubules and eventually the regeneration of new blood vessels.
Unregulated and abnormal angiogenesis may lead to various diseases. Examples of angiogenesis-related diseases that occur in pathological conditions include various cancers(tumors); vascular diseases such as vascular malformation, arteriosclerosis, vascular adhesions, and edematous sclerosis; ocular diseases such as corneal graft neovascularization, neovascular glaucoma, diabetic retinopathy, angiogenic corneal disease, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia and granular conjunctivitis; inflammatory diseases such as rheumatoid arthritis, systemic Lupus erythematosus and thyroiditis; and dermatological diseases such as psoriasis, capillarectasia, pyogenic granuloma, seborrheic dermatitis and acne (U.S. Pat. No. 5,994,292; Korean Patent Application Laid-Open No. 2001-66967; D'Amato R. J. et al., Ophtahlmol., 102:1261-1262, 1995; Arbiser J. L. J. Am. Acad. Derm., 34(3):486-497, 1996; O'Brien K. D. et al., Circulation, 93(4):672-682, 1996; Hanahan D. et al., Cell, 86:353-364, 1996).
Thus, studies on the mechanism of angiogenesis and the discovery of substances capable of inhibiting angiogenesis are of significant importance in the prevention and treatment of various diseases, including cancer. Current studies on the inhibition of angiogenesis are being performed on target genes by various strategies, including a strategy of administering a competitive substance to inhibit the action of VEGF and bFGF (basic fibroblast growth factor), which are known as potent inducers of angiogenesis, and a strategy of regulating the expression of integrin in vascular endothelial cells to inhibit the metastasis of the cancer cells. Regarding the relationship of angiogenesis with cancer, studies on the correlation between vascular absorption and angiogenesis induced by cancer cells and on proteins that induce angiogenesis are being performed but are still large incomplete. Studies on angiogenic inhibition are applicable to the diagnosis, treatment and/or prevention of a variety of angiogenesis-related diseases, and thus, there is a continued need for research and development regarding angiogenesis.
Meanwhile, βig-h3 that is an extracellular matrix protein was first isolated by differential screening of a cDNA. library made from a human lung adenocarcinoma cell line (A549) that had been treated with TGF-β1 (Skonier J. et al., DNA Cell Biol., 11:511-522, 1992). The βig-h3 protein consists of 683 amino acids and contains an amino-terminal secretory sequence and a carboxy-terminal RGD (Arg-Gly-Asp) motif serving as a ligand recognition site for several integrins (Skonier, J. et al., DNA Cell Biol., 11:511, 1992). Also, the βig-h3 protein contains four homologous internal repeat domains (designated “fas-1 domains”) which are homologous to similar motifs in the Drosophila fasciclin-I protein. Such fas-1 domains have highly conserved sequences found in the secretory and membrane proteins of many organisms, including mammals, insects, sea urchins, plants, yeast, and bacteria (Kawamoto T., et al., Biochim. Biophys. Acta, 288-292, 1998). Each of the fas-1 domains consists of 110-140 amino acids and comprises two highly conserved branches of about 10 amino acids (H1 and H2).
The βig-h3 protein is known to have a fibrillar structure and to interact with several extracellular matrix proteins such as fibronectin and collagen (Kim J.-E., et al., Invest. Ophthalmol. Vis. Sci., 43:656-661, 2002). Furthermore, the βig-h3 protein has been reported to be involved in cell growth and differentiation, and wound healing and morphogenesis (Skonier J., et al., DNA Cell Biol., 13:571-584, 1994; Dieudonne S. C., et al., J. Cell. Biochem., 76:231-243, 1999; Kim J.-E., et al., J. Cell. Biochem., 77:169-178, 2000; Rawe I. M., et al., Invest. Ophthalmol. Vis. Sci., 38:893-900, 1997; and LeBaron R G., et al., J. Invest. Dermatol., 104:844-849, 1995). In addition, the βig-h3 protein is known to mediate the adhesion of many different cell types, including corneal epithelial cells, chondrocytes and fibroblasts (LeBaron R. G., et al., J. Invest. Dermatol., 104:844-849, 1995; Ohno S., et al., Biochim. Biophys. Acta, 1451: 196-205, 1999; and Kim J.-E., et al., J. Biol. Chem., 275:30907-30915, 2000). However, there is still no report indicating that the βig-h3 protein is involved in angiogenesis.